Diabetic neuropathy is a widespread clinical problem, for which there is no FDA-approved, mechanistically based treatment. There is considerable interest in the hypothesis that neuropathy is secondary to microvascular disease in diabetic patients and drug therapies intended to induce vasodilation or angiogenesis in nerve are being explored in both pre-clinical and clinical studies. However, these systemic pharmaceutical approaches have not overcome the problem of how to target nerve blood flow without impacting vascular beds in other organs where increasing blood flow may be harmful to diabetic patients. We have therefore become interested in non-pharmacologic approaches to inducing local, rather than systemic, blood flow. Pulsed low intensity ultrasound increases local blood flow as part of its wound healing properties via both vasodilator and angiogenic mechanisms. To our knowledge, low intensity ultrasound has not undergone comprehensive preclinical evaluation of its potential to prevent or alleviate indices of diabetic neuropathy. We will address the general hypothesis that low intensity ultrasound treatment is capable of inducing biochemical and physiologic events in rat models of type and type 2 diabetes that prevent and reverse development of functional and structural indices of neuropathy via an ability to modulate local tissue blood flow. We have performed exploratory studies to investigate the effects of ultrasound treatment on nerve disorders in the streptozotocin-diabetic rat model of type 1 diabetes and found that it ameliorated nerve conduction slowing. We propose to undertake a comprehensive survey of the effects of low-intensity ultrasound on functional and structural nerve disorders in STZ-diabetic rats in both prevention and reversal paradigms and to extend optimal treatment regimens to the ZDF model of type 2 diabetes. This will be our primary goal and, while it represents a somewhat observational and high-risk approach, we believe that this is balanced by the potential for our findings to prompt an unusually rapid translation of positive preclinical observations to clinical use because of the non-invasive, non-systemic and non-drug based nature of the treatments. Our secondary goal will be to begin to investigate a potential mechanism of action, namely that ultrasound treatment induces HIF/VEGF/EPO-mediated reparative responses in the nerve in response to exaggerated nerve ischemic hypoxia induced by acute diversion of blood from nerve to muscle. By investigating a local, non-pharmacologic, approach to treating diabetic neuropathy we hope to avoid the side-effects, systemic effects and cost concerns that are inherent to current pharmaceutical-based approaches to ameliorating neuropathy in patients who are likely to require treatment for the rest of their lives. PUBLIC HEALTH RELEVANCE Our primary aim is to investigate the effect of low-intensity ultrasound to prevent and treat nerve damage in diabetic rats. Our secondary aim is to investigate whether the mechanism of action is related to induction of changes in blood flow local, without there being any general systemic effects. The goal is to determine whether this non-invasive, non-pharmaceutical, therapy has potential for rapid translation to use in patients suffering from diabetic neuropathy, for whom life-long treatment with systemic drugs designed to improve nerve blood flow may be costly and have harmful side-effects.